Another one bites the dust.

The National Center for Complementary and Alternative Medicine (NCCAM) is generally a waste of taxpayer money, but they have sponsored several well-designed large trials of popular herbal supplements. And one by one these studies have shown these popular products, such as echinacea for the common cold, to be ineffective.

To add to the list, published in JAMA this week are the results of the largest and longest trial to date of Gingko biloba for the improvement of cognitive function and to treat, prevent, or reduce the effects of Alzheimers disease or other dementia. The results of the study are completely negative.

The study was very rigorous – a consensus trial designed to address all the criticisms of prior smaller studies. It was a direct comparison of Gingko biloba at 120mg twice a day, double blind, randomized, multi-center trial involving 3019 subjects aged 72-96 for a median of 6.1 years. Subjects were followed with standardized tests of cognitive function.

The results are easy to report – every measure showed no difference between G biloba and placebo. There was no difference in cognitive function, risk of developing dementia, rate of progression of dementia or normal cognitive decline with aging. Usually such studies involve some random noise in the results, especially when several outcomes are measured. But with such a large study, random fluctuations should average out, and that is exactly what happened.

Gingko biloba has been used for centuries as a medical herb, and the most popular claim made for its use was to enhance cognitive function. The justification for this claim was always thin – G biloba has a mild blood thinning effect. It was therefore claimed that the herbal drug would enhance blood flow to the brain and improve brain function.

However, this is not a plausible mechanism. The brain exquisitely regulates its own bloodflow, and suboptimal perfusion results in a widening of the blood vessels to increase flow. This autoregulation would not be enhanced by mild blood thinning in a healthy individual.

In someone with severe atherosclerosis or narrowing of the arteries, to the point where autoregulation of blood flow is not able to optimize perfusion of brain tissue, the result is typically stroke-like symptoms. In this situation a blood thinner may improve perfusion, and generally drugs like aspirin are prescribed.

This, of course, implies that if simple blood thinning could improve cognitive function, then aspirin would be more effective at this than G biloba. In any case, this putative mechanism was never very plausible.

More recent studies have found that G biloba has some anti-oxidant effects. However, anti-oxidants as a class have not been found to be effective for cognitive function or any other clinical outcome. So this too lacks plausibility.

It was also found that G biloba can reduce amyloid aggregation. Amyloid plaques build up in the neurons of patients with Alzheimers disease, so this is a plausible mechanism for slowing the progression of some forms of dementia. However, as we now know this does not translate into a measurable clinical effect.

The lessons from this study and the lack of effect for Ginkgo biloba should learned and generalized.

Historical use of an herbal drug is not sufficient evidence for its effectiveness.

Preliminary, small, or poorly designed studies are unreliable, and often result in false positives. Only large definitive trials are reliable.

Finding a potential mechanism for a drug, herbal or otherwise, is not a sufficient basis for a clinical claim – you need clinical trials with actual people to support such claims. Further, if researchers go looking for potential mechanisms to explain a putative action of a drug or supplement, it is not surprising that they will find some. Drugs typically have many biochemical actions in the body, and finding an effect is not surprising. There is also likely confirmation bias and the file-drawer effect at work – favoring the publishing of interesting and positive studies.

In the end – all the ancient wisdom, small studies, and putative mechanisms meant nothing. They were all trumped by a large and impeccably designed study that shows Gingko biloba is of no measurable benefit for cognitive function.

These results call into question the practice in many countries of allowing pharmacological agents like G biloba to be marketed as supplements with health claims prior to being adequately studied. The European and US markets for G biloba are in the hundreds of millions of dollars per year. It will be interesting to see what happens following this study.

The study did find that G biloba was generally safe. However, it should be noted that G biloba, although sold in the US as a supplement, should be considered a drug. It does have an anti-platelet blood-thinning effect and should not be taken prior to surgery. However, because many people think of herbs as supplements and not drugs, patients rarely disclose their supplements to their doctors, and doctors fail to take a supplement history. Safety is therefore still an issue.

Herbs and botanicals have been and can be a valuable source for useful pharmacological agents. However, regulating and using them as supplements has many flaws – as the history of Gingko biloba once again highlights.